Radiotherapy and chemotherapy often disrupt the taste system of cancer patients, leaving them with little or no ability to taste foods. These deficts can cause poor dietary intake, malnutrition and a poorer prognosis for recovery from cancer. However, recent studies suggest that these therapies disrupt the normal cell renewal cycle of taste cells in adult taste buds. Adult taste sensory cells have a life span of 8-12 days and are continuously replaced but the mechanisms responsible for this cell replacement cycle are not well understood. During embryonic development, the Wnt-?-catenin signal pathway plays an important role in cell differentiation and maturation. However, new evidence suggests that Wnt-?-catenin signaling may also play an important part in the adult taste cell replacement cycle and in restarting this cycle after injury from irradiation. The proposed research will examine the role of the Wnt-?-catenin signal pathway in the adult taste cell replacement cycle and how irradiation affects this role. One experiment will use mice with a Wnt reporter allele to mark cell in which Wnt-?-catenin signaling is active to assess changes in signaling after irradiation. Nguyen and Barlow (2008) reported that after a single 8 Gy dose to the head and neck of mice: 1) proliferation of taste bud progenitor cells is temporarily (1-3 days) arrested, interrupting the supply of new cells migrating into taste buds, 2) non-proliferating cells are lost from taste buds after 7 days, and 3) restoration of taste function occurs after 14 days. We will compare the taste buds of normal and irradiated mice to determine when expression of this signal pathway is altered by irradiation. Another set of experiments will determine if conditional inhibition of the Wnt-?-catenin pathway decreases the ability of the taste epithelium to recover following irradiation. We will use a conditional bigenic system in mice fed doxycycline to drive the expression of the Wnt secreted inhibitor, Dkk1 in lingual epithelium. Control and irradiated bigenic mice will be compared over 14 days to test the hypothesis that inhibition of Wnt-?-catenin signaling will retard or repress recovery of taste cell renewal. This project will yield ne insights into the processes underlying how taste buds are repopulated through proliferation, regeneration, and maturation of adult taste cells after injury. This research will provide the basi for future research to study how the normal adult taste bud system is maintained, how it is affected by injury from irradiation, chemotherapy drugs, or the combination of the two therapies, and to develop potential ways of facilitating recovery or even protecting taste cells from the deleterious effects of cancer treatments or from other types of injury. PUBLIC HEALTH RELEVANCE: Radiotherapy and chemotherapy often leaves the cancer patient without the ability to taste foods, leading to malnutrition and a poorer prognosis for recovery from cancer. Recent studies suggest that these therapies disrupt the replacement of taste sensory cells. The proposed research will study how the Wnt-?-catenin signaling pathway contributes to the taste cell renewal and regeneration cycle of the adult taste system and how irradiation disrupts this pathway. It may eventually help determine how to facilitate recovery or even protect this system from the effects of these therapies.